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AcrAB-tolC Efflux Pump Genes in E. coli
Background Efflux pumps are proteins or groups of proteins that when combined act as a way for a cell to transport harmful compounds through the membrane out of the cell. In the case of the AcrAB-TolC efflux pump system, three proteins are combined to form a pump that spans the entirety of the cell membrane. When functioning, the pump relies on the proton motive force to generate the force required to push harmful chemicals out of the cell. Naturally, the AcrAB-TolC system has evolved to transport hormones or bile and fatty acids, but the pump is also capable of removing different types of harmful antibiotics that manage to enter the cell. Piddock, Laura JV. "[http://www.nature.com/nrmicro/journal/v4/n8/abs/nrmicro1464.html Multidrug-resistance efflux pumps? not just for resistance]."''Nature Reviews Microbiology'' 4.8 (2006): 629-636. Regulation The regulation of AcrAB-TolC is controlled by the MarA, SoxS and Rob multiple antibiotic resistance (MAR) network. Ruiz, Cristian, and Stuart B. Levy. "[http://jac.oxfordjournals.org/content/early/2013/09/15/jac.dkt352.short Regulation of acrAB expression by cellular metabolites in Escherichia coli]." ''Journal of Antimicrobial Chemotherapy'' (2013): dkt352. This three protein multiple antibiotic resistance network is responsible for controlling many of the stress responses within the cell. There are so many connected nodes in the network that the complete regulation system has not been completed as of yet. What is known, however, is that the MAR network responds very efficiently to stress signals produced by the cell. Once the MAR network is activated, many downstream genes (such as AcrAB-tolC) respond to mitigate the stress. ] Specifically what is happening in the case of AcrAb-tolC is shown in the figure to the right. There appear to be three main pathways by which AcrAB production is triggered. The first is by repressing AcrR, the gene that naturally represses AcrAB. In this case, cellular metabolites block production of AcrR and this allows for production of AcrAB. Another mechanism of AcrAB production is via SoxS activation. In the presence of metabolites, SoxR is activated which in turn activates SoxS. SoxS is then available to activate expression of AcrAB. Finally the last proposed AcrAB activation mechanism is via MarA itself. Cellular metabolites bind to MarR and that prevents MarR from repressing the marRAB operon. MarA is then freely produced which then activates the acrAB operon. A few things worth mentioning are that first, metabolites are not the only thing that this genetic network responds to. As mentioned previously, many compounds capable of inducing stress within the bacteria can trigger the MAR network. Also it is important to note that once the triggers of stress are gone, the acrAB operon will cease production. Reasons for MAR Regulation From an evolutionary standpoint, its interesting that there are so many different pathways that can trigger the MAR network and subsequently trigger efflux pump expression. One potential reason for this is that the AcrAB efflux pump system can export so many different types of molecules, there are different triggers for all of those different molecules. Each activator may respond to different types of molecules. Another potential reason for why the MAR network is designed in this manner is that perhaps AcrAB is extremely vital to the cell's survival. Each activator could be thought of as a fail-safe system where perhaps if there is a mutation rendering one activator useless, there is another MAR activator that is just as capable to get the job done. References